Direct compression tabletting composition and pharmaceutical tablets produced therefrom

ABSTRACT

Method for producing a direct compression vehicle for tabletting which involves admixing a crystalline sugar with a maltodextrin and spraying the admixture with an aqueous solution of a maltodextrin. The resulting vehicle may be combined with a pharmaceutically active ingredient wherein the pharmaceutically active ingredient may be present in an amount of up to 80% of the weight of the vehicle. The resulting pharmaceutical composition can be compressed into a tablet having a Strong Cobb Hardness Unit (S.C.H.U.) value of at least about 6.

United States Patent [1 1 Kanig 1 DIRECT COMPRESSION TABLETTINGCOMPOSITION AND PHARMACEUTICAL TABLETS PRODUCED THEREFROM [75] Inventor:Joseph L. Kanig, Westbury, NY.

[73] Assignee: CPC International Inc., Englewood Cliffs, NJ.

[22] Filed: Sept. 27, 1973 [21] Appl. No.: 401,322

[52] US. Cl 424/127, 424/154, 424/155,

[51] Int. Cl. Cl3f 3/00 [58] Field of Search 127/29, 30, 63; 426/214,426/217, 213; 424/127 [56] References Cited UNITED STATES PATENTS3,140,201 7/1964 Reimers 127/30 X 3,169,888 2/1965 Ryan 127/30 3,305,4472/1967 I Reimers... 127/30 3,589,909 6/1971 Godzicki 426/214 3,619,29211/1971 Brouillard 127/29 3,627,583 12/1971 Troy 426/217 X 3,639,1682/1972 Monti 127/29 Mar. 25, 1975 3,639,169 2/1972 Broeg 127/293,642,535 2/1972 Graham 127/29 FOREIGN PATENTS OR APPLICATIONS 1,286,27523/1912 tinged Kingdom OTHER PUBLICATIONS H. David Bergman et a1., Drugand Cosmetic Industry, 109(3), 48, 50, 56, 58, 156, 157, (Sept. 1971).

Primary Examiner-Morris O. Wolk Assistant ExaminerSidney Marant;Attorney, Agent, or FirmAlbert P. l-Ialluin 57 ABSTRACT Method forproducing a direct compression vehicle for tabletting which involvesadmixing a crystalline sugar with a maltodextrin and spraying theadmixture with an aqueous solution of a maltodextrin. The resultingvehicle may be combined with a pharmaceutically active ingredientwherein the pharmaceutically active ingredient may be present in anamount of up to 80% of the weight of the vehicle. The resultingpharmaceutical composition can be compressed into a tablet having aStrong Cobb Hardness Unit (S.C.H.U.) value of at least about 6.

25 Claims, N0 Drawings DIRECT COMPRESSION TABLETTING COMPOSITION ANDPHARMACEUTICAL TABLETS PRODUCED THEREFROM BACKGROUND OF THE INVENTION 1.Field of the Invention:

This invention relates to direct compression tabletting compositions andthe pharmaceutical tablets produced therefrom. More particularly, thisinvention relates to an improved direct compression tablettingcomposition prepared from a uniquely granulated mixture of a crystallinesugar such as dextrose monohydrate, and a maltodextrin having ameasurable dextrose equivalent value not substantially above about 20.The improved direct compression tabletting compositions are capable ofbeing directly compressed into commercially acceptable and hard tabletswith large amounts of a variety of active materials. The new directcompression tablets can be used as the sole binder disintegrant withoutthe aid of other adjuvants ordinarily used for this purpose.

2. Description of the Prior Art:

The compressed tablet is the most popular unit dosage form for medicinalsubstances. The tablet as a dosage form can be traced to well over 1,000years ago when a procedure for molding solid forms containing medicinalingredients was recorded. As a result of the introduction of newcarriers and compression vehicles, tablets are replacing all forms ofpills, powders and capsules. Accordingly, tablets presently representthe largest production volume of all pharmaceuticals.

The reason for the widespread use of tablets is apparent, since tabletsenable: (1) administration of medication in an accurate dose, (2) fastand accurate dispensing with less chance of error and contamination, (3)ease of administration, (4) administration in a form in which the timeand area of contact between'the active ingredient and the taste buds isreduced, thus obviating the physiological problems associated with theoral administration of drugs that possess a bitter taste and, in thecase of coated tablets, with drugs that possess a dis agreeable odor,(5) release of drugs at specific loca tions in the gastro-intestinaltract to: (a) prevent degradation of drugs sensitive to the low pHenvironment in the stomach, (b) prevent release of drugs that irritatethe gastric mucosa in the stomach, (c) facilitate local action orpreferential absorption at specific sites in the tract, (6) enhancestability by effecting a marked reduction in the surface of the drugexposed to the environment, (7) rapid production, and (8) economy andease in storage, packaging and shipping.

It is well-known that in order to form a tablet of a given material, thematerial must possess fluidity and compressibility. lt is essential thatthe material must flow uniformly from the hopper to the dies of thetablet press. Any defective flow of the material will effect the weightof the tablets, content uniformity, disintegration time, hardness,friability, and also the bioavailability of the active ingredient.

There are currently three basic methods for tablettin g. They are thewet granulation method, the dry granulation method, and the directcompression method. The direct compression method is by far the desiredmethod from the standpoint of processing procedures, equipment andmaterials. However, only a very limited number of pharmaceutically usedsubstances possess enough cohesive strength and flowability to allowdirect compression without previous granulation. Certain crystallinematerials, such as potassium bromide and potassium chloride can becompressed without preliminary treatment. Also, aspirin, phenolthaline,chlorohydrate can be directly compressed.

It has been stated that the ideal material to compress would be composedof crystals which, at the moment of compression, behaved like clayrather than rubber. The crystals should be such that on release ofpressure they should not rebound into their original shape. Generally,most materials possess both plastic and elastic deformation properties.Therefore, most materials are not suitable for direct compressionwithout previous granulation.

It has been estimated that about 20% of the materials used fortabletting in the pharmaceutical field may be compressed directly. Inorder to use this method to a considerable extent, many more materialsshould be modified by treatment or by use of additives. Modification maybe undertaken, either by treating the material in some special wayduring earlier stages of preparation, or by adding a binder or excipientmaterial which will surround the active ingredient and form an easilycompressible carrier.

An ideal direct compression vehicle should possess the followingproperties: (1) low elastic modules, (2) high dislocation density, (3)inert, non-potent and nontoxic, (4) high degree ofplastic deformation,(5) colorless, odorless, tasteless or without disagreeable taste, (6)free-flowing, (7) compatible with active ingredients and commonadditives like lubricants, colors, etc., (8) non-hygroscopic, orrelatively low order of hygroscopicity, (9) fast disintegrationproperties, or should not delay the bioavailability of the drug, l0)limited range of particle size distribution, l l) stable effects ofaging, and (12) reworkable and should possess high carrying capacity foractive medicinal agents.

There are currently several available direct compression vehicles. Theyinclude spray-dried lactose; anhydrous lactose; microcrystallinecellulose; dicalcium phosphate dehydrate, unrnilled; Cellutab;spraycongealed mannitol; Emcompress; Magnapol', Frodex; Di Pac; andRoyal-T.

Microcrystalline cellulose is a natural cellulose in a speciallyprocessed form which makes it digestible. lt normally produces goodtablets with fast disintegration and drug release properties. lt hasbeen found to give better results if stored in a dry condition beforeuse exposure to a slightly humid atmosphere makes it compress lesseasily. It is quite fluffy by nature.

Spray-dried lactose has a heavy appearance when poured and is sphericalin shape. It cannot be re worked, as the spherical shape is lost whenground. lt has been disclosed that spray-dried lactose with 5-10% maizestarch as a disintegrant and 0.5% magnesium stearate as a lubricantforms a useful direct compression base. However, it has the tendency toget brown in the presence of moisture, amines, phosphates, lactates andacetates. Borates and the stearate lubricants tend to retard thebrowning.

Dicalcium phosphate dehydrate has good flow and compressibilityproperties. The tablets from dicalcium phosphate are also easilyembossed. The increased flow is believed to be due to its high density.It cannot be re worked. Due to its alkaline pH, stability of ingredientslike Vitamin C or aspirin may be effected.

The vehicle mannitol, absorbs heat from the surroundings when going intosolution, and results in good mouth feel." Thus, it is commonly used inchewable tablets. It has been reported that a change in the compressioncharacteristics of mannitol occurs when spraycongealing the product.

The vehicle known in the art as Cellutab is a spraydried dextroseproduct. It has excellent flow characteristics. It is relatively coarsecompared to other vehicles and contains approximately 8% moisture.

The product known in the art as Encompress is essentially a blend ofdicalcium phosphate dehydrate, unmilled; starch; Avacil; and magnesiumstearate. It is free-flowing, self-lubricating and possesses goodcompression characteristics.

The vehicle known in the art as Royal-T is essentially an agglomeratedmixture of a crystalline sugar such as dextrose and a maltodextrin suchas Mor-Rex Code 1918. The preparation of this bold and new pioneeringdiscovery in the direct compression vehicle art is described in BritishPat. No. 1,286,275, published Aug. 23, 1972 which generally correspondsto pending U.S. application Ser. No. 485,480, filed July 3,1974, whichis a continuation-in-part of abandoned U.S. application Ser. No.254,552, filed May 18, 1972, which in turn is a continuation-in-part ofabandoned U.S. application Ser. No. 141,030, filed May 6, 1971, andwhich in turn is a continuation-impart of abandoned U.S. applicationSer. No. 767,520, filed Oct. 14, 1968.

The vehicle known in the art as Di Pac is also a mixture of acrystalline sugar and a maltodextrin. The preparation ofthis product isgenerally described in the aforesaid British patent and, morespecifically disclosed in U.S. Pat. No. 3,642,535, granted Feb. 15,1972.

Although the direct compression method for preparing tablets is by farthe method of choice by virtue of its simplicity, this method hasseveral limitations which have hampered its use in the tablettingindustry. These limitations include: (1) differences in the particlesize, and bulk density between the diluent and the active ingredient maylead to stratification and variation in drug content of tablets, (2)unless the drug itself is easily compressible, the amount present islimited to a maximum of 25% of the tablet weight (Of course, the amountof vehicle and the weight of the tablet may be increased to reduce thepercentage of active ingredient. Then there arises a question ofeconomics and size of the tablet, a question that may be resolved onlyby wet granulation), (3) the drug may interact with the vehicle, such asamine compounds do with spray-dried lactose, and (4) static chargeswhich may develop on the drug during combination and mixing may preventuniform distribution.

In light of the limitations mentioned hereinabove, the great percentageof tabletting operations, therefore, have been forced to resort to otherformulation techniques such as the wet and dry granulation methods.Thus, there is a continued search for an improved direct compressiontabletting composition capable of being employed as a binder in thepreparation of tablets by direct compression which are rapidlydisintegrative, resistant to breakage and crumbling and compatible withthe active material incorporated therein which forms the basis of thecompositions utility.

SUMMARY OF THE INVENTION measurable dextrose equivalent value notsubstantially above about 20 to form a uniform admixture and thereafterconcurrently agitating and spraying said admixture with an aqueoussolution containing dissolved therein the aforesaid maltodextrin havinga measurable dextrose equivalent value not substantially above about 20,said aqueous solution of dissolved maltodextrin being present in anamount sufficient to provide a damp mass of said uniform admixture andto cause binding and granulation of said uniform admixture. Thegranulated mixture is thereafter dried to a moisture content of lessthan about 10% by weight.

The preferred direct compression compositions of this invention willcontain from about 15% to about 35% by weight of said maltodextrin,preferably from about 20-30% by weight of said maltodextrin. Thepreferred crystalline sugar utilized includes dextrose monohydrate.

It has been found that when a crystalline sugar such as dextrosemonohydrate is granulated with at least about 15% by weight of amaltodextrin having a measurable dextrose equivalent value notsubstantially above 20, the composition has an exceptionally highcarrying capacity for a large variety of pharmaceutically activecompounds. This result is quite unexpected, inasmuch as the compositionsdescribed in British Pat. No. 1,286,275 have a relatively low carryingcapacity for most pharmaceutically active compounds. Thus, thecompositionsof this invention provide a direct compression vehicle whichcan be directly compressed into commercially acceptable and hard tabletswith large amounts of a variety of active materials and can be used asthe sole'binder disintegrant without the aid of other adjuvantsordinarily used for this purpose.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The crystalline sugars employedin the practice of the present invention include any type of crystallinesugar product, examples of which include dextrose, sucrose, lactose andblends thereof. Many of these crystalline sugars are wellknown in theart and are conventional articles of commerce sold under various tradenames. Such sugars are generally produced and crystallized byconventional techniques. The preferred crystalline sugar employed in thepractice of the present invention is dextrose, either in itsmonohydrate, anhydrous or dehydrated form. Dextrose monohydrate isparticularly preferred as the crystalline sugar to be utilized in thepractice of the invention.

The maltodextrins having a measurable dextrose equivalent value notsubstantially above about 20 utilized in the practice of the presentinvention represent a known class of materials. The maltodextrins arealso known as hydrolyzed cereal solids and such materials arecommercially available under the tradenames Mor- Rex, manufactured andsold by CPC lnternational lnc., Maltrin. manufactured and sold by GrainProcessing Corporation, Frodex, manufactured by American- Maize ProductsCompany, and Star-Dry l5, manufactured by A. E. Staley ManufacturingCompany.

The terms maltodextrins" and hydrolyzed cereal solids" herein refer tothose starch conversion products having a relatively small amount ofdextrose and maltose. Generally, the dextrose content of themaltodextrins in less than about 2.4% by weight and the amount ofmaltose is less than about 9% by weight. As it is wellknown in theindustry, the dextrose equivalent value in a starch conversion producthaving a value above about 20 is generally referred to as a corn syrupsolid; whereas starch conversion products having only a trace amount ofdextrose are referred to as dextrins. The starch conversion productshaving a measurable dextrose equivalent value not substantially aboveabout 20 and also having a trace amount of dextrose as hereinabovereferred to, are known as hydrolyzed cereal solids or maltodextrins. ltis the maltodextrins described hereinabove which are employed in thepractice of this invention for the preparation of the direct compressiontabletting compositions. The corn syrup solids having a dextroseequivalent value greater than about 20 are not suitable in the practiceof the present invention, since these products do not possess the properproperties to effectively cause granulation and thereby produce atabletting composition having a high carrying capacity for the activematerial. The corn syrup solids are also extremely hygroscopic, aproperty undesirable from the standpoint of flowability and mixingduring the direct compression procedure for preparing the tablets.

The preferred maltodextrins or hydrolyzed cereal solids employed in thepractice ofthe present invention are characterized as having adescriptive ratio of at least about 2. The descriptive ratio is the sumof the percentages (dry basis) of saccharides of the maltodextrin with adegree of polymerization of l to 6 divided by the dextrose equivalentvalue. An especially preferred class of maltodextrins employed in thepractice of the present invention are derived from waxy starchhydrolysates and have a dextrose equivalent value in the range of fromabout 9 to about 13 and a descriptive ratio of at least about 2. Thesestarch hydrolysates or maltodextrins are prepared by the methoddisclosed in British Pat. No. 1,203,048, particularly Examples 111 andIV, and the corresponding disclosure and claims in U.S. application Ser.No. 181,566, filed Sept. 17, 1971, US. Pat. No. 3,849,194, granted Nov.-19, 1974 the disclosure of which is incorporated herein by reference.These waxy starch hydrolysates or maltodextrins are commerciallyavailable under the tradename of Mor- Rex Code 1918, manufactured andsold by CPC lnternational Inc.

The term measurable dextrose equivalent value (D.E,) referred to herein,is defined as the reducing value of the hydrolysate material compared tothe re as percent, dry basis, i.e.,

Reducing Value of Hydrolysate Material Reducing Value of Dextrose x Inthe above equation, an equal Weight of each of dextrose and thehydrolysate material is involved. The term dextrose equivalent value ofa starch hydrolysate is a common expression in the art for describingthe total reducing sugars content of a material calculated as dextroseand expressed as percent, dry basis.

An essential aspect of the invention comprises admixing (e.g., byspraying or by any other convenient means) an aqueous solutioncontaining from about 5 to about 60 weight/volume percent of theabovedescribed maltodextrin with a uniform mixture of a crystallinesugar and 10 to about 50% by weight of the above-described maltodextrin.The admixing of the aqueous solution of the maltodextrin should beconducted while the uniform mixture of the crystalline sugar and themaltodextrin is being agitated to achieve uniform and homogeneouscontactof the crystalline sugar particles and the maltodextrin with the aqueoussolution containing the maltodextrin. Preferably, the aqueous solutionwill contain from about 10 to about 30% weight/volume of themaltodextrin.

The solution containing the maltodextrin is preferably admixed with theuniform mixture of the crystalline sugar and maltodextrin at ambienttemperatures and pressures. Slight deviations may be imposed, providedthat such conditions do not adversely affect the compositions.

The amount of the solution containing the maltodex trin utilized mayvary, depending on the characteristics of the crystalline sugar, theamount of moisture in the homogeneous mixture of the crystalline sugarand/or the maltodextrin, etc. Generally, the amount of the aqueoussolution containing the maltodextrin utilized will be an amount suchthat its admixture with all of the materials provides a thoroughlyadmixed damp mass. Such amounts will generally be in the range of fromabout 20 ml. to about ml.' of the aqueous solution per one kilogram (kg)of the uniform mixture of the crystalline sugar and the maltodextrin. Asuitable damp mass can be obtained under ordinary conditions utilizingfrom about 40 ml. to about 60 ml. of the aqueous solution per onekilogram (kg) ofthe uniform mixture.

After the aqueous solution containing the maltodextrin is added to theuniform mixture of the crystalline sugar and the maltodextrin, theentire admixture is thoroughly mixed to cause granulation. Thegranulated product is thereafter dried to a moisture content of lessthan about 10% by weight, preferably less than about 5% by weightmoisture. The dried granulated product may be screened to provide a morehomogeneous screen size. The final dried and screened product can beused as is as a direct compression tabletting composition whereupon itcan simply be admixed with the desired active material and directlycompressed into tablets.

The crystalline sugar hereinabove described may be admixed in either dryor wet form with the maltodextrin. Preferably, the crystalline sugar,e.g., dextrose monohydrate, is employed in its centrifuge cake formfollowing crystallization, which cake has been washed and centrifuged sothat the water content in the cake (excluding water of hydration, which,if present, comprises l-l6% of the cake weight) will be sufficient toprovide the necessary amount of water to initially granulate thecrystalline sugar with the maltodextrin. In this respect, the amount ofwater necessary to initially granulate the above-described compositionof this invention, excluding water of hydration, is preferably from 1-8%by weight of the total composition. The initially granulated admixturemay be dried, providing the amount of maltodextrin exceeds about 10% byweight of the total mixture. However, it has been found that in order toprovide a direct compression vehicle having a high carrying capacity, itis necessary to spray the admixture of the crystalline sugar andmaltodextrin with an aqueous solution containing dissolved therein atleast about 5% weight/volume of the maltodextrin.

As stated hereinabove, the amount of maltodextrin employed in the directcompression compositions of this invention is critical. The finalcomposition will generally contain more than about by weight of themaltodextrin which is introduced into the matrix of the crystallinesugar composition, either by the initial blending of the maltodextrinwith the crystalline sugar and/or by the admixture treatment with theaqueous solution containing the maltodextrin which follows the blendingof the crystalline sugar and the maltodextrin. Preferably, thetabletting composition will contain from about to about 35% by weight ofthe maltodextrin based on the total amount of the direct compressionvehicle. Particularly good results are obtained when the level ofmaltodextrin in the tabletting composition is in the range of from aboutto about by weight.

In one typical example of the above-described process of preparing thedirect compression tabletting compositions of the present invention, apremix is formed by admixing 80 parts by weight of dextrose monohydratecrystals and 20 parts by weight of maltodextrin having a dextroseequivalent value in the range of from about 9 to about 13, the watercontent of the mixture being in the range of from about 2 to about 15 byweight. The mixture is thereafter thoroughly agitated and sprayed withan aqueous solution containing the above-described maltodextrin in anamount such that a damp mass is formed. The amount of maltodextrindissolved in the aqueous solution is preferably l0 to about 40%weight/volume. In a typical example, 50 ml. of a 20% weight/volumeaqueous solution contain ing the aforedescribed maltodextrin is sprayedonto 1 kg. of the dextrosemaltodextrin admixture (800 grams of dextroseand 200 grams of maltodextrin). The sprayed mixture is thereafter driedto a moisture content of less than about 10%, preferably less than about5% by weight. Alternatively, the granulated mixture may be wet screenedthrough a number 6 sieve prior to drying to the final desired moisturecontent. However, satisfactory results are obtained by drying thegranulated mixture prior to screening.

The particle size of the direct compression tabletting composition ofthe present invention is rather impor tant. Most pharmaceuticalcompounds have a particle size of less than 100 mesh. Accordingly, thecarrier must be coarser or have a particle size larger than thepharmaceutical compound. If the particle size of the direct compressiontabletting composition or vehicle is v broadly dispersed, stratificationwill occur and uniform amounts of ingredients in the respective tabletswill not be successfully accomplished. Therefore, it is important thatthe particle size of the direct compression tabletting compositions ofthe present invention have a relatively narrow particle sizedistribution. The particle size distribution found to be most desirableshould be such that the particles of the composition fall within therange of 20 to about +200. However, better results are obtained whereinthe composition has a particle size in the range from about 30 to aboutand, more preferably, in the range of from about -40 to about +100.

In the preferred preparation of pharmaceutical tablets by the presentinvention, an active material ingredient is thoroughly mixed by anysuitable dry blending technique with the above-described directcompression tabletting composition in relative amounts required toprovide a resultant superficially dry, free-flowing formulation directlycompressible into tablets, and the formulation is then tabletted bydirect compression.

Active ingredients contemplated to be employed in the preparation oftablets by the present invention constitute all active ingredientscompatible with the abovedescribed direct compression tablettingcompositions. The present invention is particularly suitable for the usein preparing tablets containing the well-known pharmaceutically activematerials. Specific examples of pharmaceutically active ingredientswhich advantageously may be tabletted by the present invention includeascorbic acid, sodium salicylate, acetaminophen, sodium bicarbonate,aluminum hydroxide, magnesium trisilicate, Vitamin E acetate, calciumlactate, ferrous sulfate and mixtures thereof.

Particularly preferred pharmaceutically active mate rials includeascorbic acid (Vitamin C), acetaminophen (APAP), aluminum hydroxide incombination with sodium bicarbonate (an antacid); citric acid incombination with sodium bicarbonate (an antacid), and magnesiumtrisilicate in combination with aluminum hydroxide (in a ratio of 2:1,respectively, as another antacid).

The pharmaceutically active materials may be present at relatively highlevels in the tablets produced from the vehicles of the presentinvention. These tablets, even when they contain a high level of theactive material, possess acceptable hardness and friability values, notpossessed by other sugar-based tablets such as those described inBritish Pat. No. 1,286,275. The tablets of the present invention may beprepared by direct compression utilizing relatively small amounts ofpressure in high speed tabletting machines. Due to the unusualstructural integrity of the direct compression tabletting vehicles ofthe present invention, the vehicles may be simply dry mixed with thedesired active materials, and, alternatively with conventionaltabletting aids such as fillers, lubricants and the like, to obtain active ingredient-containing formulations which are directly compressibleinto tablets in conventional tabletting equipment. These directlycompressed tablets exhibit the desired hardness and friability eventhough they are sugar-based compositions. The fact that the tablets aresugar-based and also contain the new relatively tasteless maltodextrinsrenders the tablets quite suitable for chewable type formulations. Inother words, the sugar in the tablets masks the undesirable flavor ofmany active materials. Thus, the present invention provides pleasanttasting chewable tablets which may contain a high level of activematerial therein and still have the appropriate hardness and friabilitynecessary for commercial manufacture and shipping of these tablets.

The novel tabletting vehicles of the present invention are alsocharacterized as having properties which satisfy the requirements of abinder for the active material and a disintegrant for the tablet in anaqueous medium. Thus, the compositions of the present invention arecapable of being directly compressible into tablets having commerciallyacceptable hardness, friability and disintegration properties merely byblending the compositions of the present invention with an activematerial and compressing the mixture with conventional tablettingequipment.

The actual reason why the novel tabletting vehicles of the presentinvention are capable of carrying relatively high levels of activematerials and still maintain commercially acceptable hardness.friability and disintegration properties when directly compressed at lowpressures is not fully understood. These unusual properties are not asevident in the agglomerated" dextrose-maltodextrin tablettingcompositions described in British Pat. No. 1,286,275. Not wishing to bebound by any theory, it is believed, however, that the addition of theaqueous solution containing the maltodextrin dissolved therein to theuniform mixture of the crystalline sugar and maltodextrin achieves aform of granulation which provides a unique structural integrity in thevehicle. This structural integrity, it is believed, provides a matrixwhereby the active material can be locked therein and the resultingcomposition thereby uniquely possesses a low elastic modules, a highdislocation density and a high degree of plastic deformation. Since thevehicles of the invention are free-flowing, nonhygroscopic andcompatible with active ingredients and common additives, as well ashaving fast disintegration properties, they are excellent directcompression vehicles.

The unique structural integrity of the direct compression vehicles ofthe invention which makes it possible for the granulated mixture ofacrystalline sugar such as dextrose and from about to about 50% by weightof a water soluble maltodextrin having a measurable dextrose equivalentvalue not substantially above about 20, wherein said granulated mixturecontains less than about 10% by weight moisture, to be capable of beingformed into hard, substantially non-friable tablets by directcompression when in admixture with up to 80% by weight of at least onepharmaceutically active ingredient, said tablets have a Strong CobbHardness Unit Value (S.C.H.U.) of about 6 or more, and are substantiallynon'friable.

ln many instances, the tablets of the invention which contain theaforesaid active ingredients will have a hardness value greater thanabout 7 S.C.H.U. and quite often greater than about 9 S.C.H.U. Thehardness values referred to herein are generally obtainable bycompressing the dry blended vehicle of the present invention with theactive material at pressures as low as 2,000 pounds and, moreconsistently, such hardness values are obtained when the dry mix iscompressed at pressures of 3,000 5,000 pounds (as is generally the casein some commercially available tabletting machines). The hardness andfriability properties are further improved when the level ofmaltodextrin is increased to a value of from -35%, the most preferredlevels being in the range of from about 30% by weight.

A preferred embodiment of the invention comprises 21 directly compressedpharmaceutical composition in tablet form, comprising a dry-blendedmixture of up to about 80% by weight of a pharniaceutically activeingredient such as ascorbic acid or acetaminophen and at least about 20%by weight of a granulated mixture of dextrose and about 15 to about 35%by weight of a water soluble maltodextrin having a measurable dextroseequivalent value not substantially above about 20, said granulatedmixture containing less than about 10% by weight moisture, said directlycompressed pharmaceutical composition having a Strong Cobb Hardness Unit(S.C.H.U.) value of at least about 6. Typically, the preferred tabletsof the invention will contain from about 15 to about 35% by weight ofthe pharmaceuti cally active ingredient. Of course, the level of activeingredient in the tablet having the desired hardness value will varyfrom one active ingredient to another. For example, higher levels ofascorbic acid can be tolerated as compared to Vitamin E acetate toattain the desired hardness values with the vehicles of the presentinvention at comparable pressures of preparation. In any event, it isquite unexpected that a crystalline sugar such as dextrose based vehicleis capable of providing substantially non-friable, hard tablets whendirectly compressed with high levels of active ingredients.

As mentioned hereinabove, various known additives such as lubricants,fillers, colors and disintegrants may be added to the novel vehicles ofthe present invention for their known purposes. Such additives includemagnesium stearate, talc, CabO-Sil, Cellutab, Sta-Rx 1500, Magnapol,etc. These additives may be present in amounts ranging from about 0.25%by weight to about 10% by weight or more. The amount of additive, suchas the suitable libricant, will generally depend on the active materialemployed, and the speed and pressure of the tabletting machine utilized.

Because of the plethora of terms that are in common use in the art, afew definitions are made to simplify the present application and permitit to be more concise.

The terms tablet hardness", tablet friability, weight variation, tabletdisintegration, and accelerated stability study are defined as follows:

Tablet Hardness A measure of the strength of tablets (average of ten ormore tablets) and their ability to retain their physical integrity,expressed in terms of Strong Cobb Hardness Units (S.C.H.U.), asdetermined by conventional procedure using a Strong Cobb Hardness testerof the Strong-Cobb-Arner Company, Cleveland, Ohio, and the average ofthese readings is reported herein as mean hardness. The hardness testerwas actuated by hand at 60i 5 strokes per minute.

Tablet Friability A measure of the tendency of tablets (average of 10 ormore tablets) to crumble and dust, expressed in terms of percent weightloss, as determined by the R0- che test described in the Journal of theAmerican Pizarmaceutical Association, Scientific Edition, Vol. 45, pages114-116 (1956). This is conducted by sampling ten or more tablets fromeach batch by first de-dusting the tablets and weighing the same. Thetablets are then subjected to the friability test in a Roche Friabilatorat 20 revolutions per minute. The tablets are allowed to roll and fallfor 4 minutes and thereafter de-dusted and weighed again. The loss ofweight is reported as percentage loss from the original weight. lt iswell-known that an active ingredient-containing tablet displaying aweight loss of less than about 1% generally is considthe mean of thesetwo limits is taken.

ered to have acceptable friability. Such a tablet characteristic isherein defined as substantially non-friable.

Weight Variation This test is conducted by accurately weighing or moretablets from a batch on a Mettler Balance and the high and low limits ofthe tablet weights are noted and The time observed for tablets (range ofsix tablets) to disintegrate in water, as determined by a modification,in which the use of this is eliminated, of the procedure for uncoatedtablets described in Pharmucopeia of the United States ofAmerica, 16th.Edition, pages 934-936 I960).

The pressure-hardness profiles were obtained from several dextroseproducts and Royal-T (agglomerated" mixture of dextrose monohydrate wetfilter cake and about 5% by weight Mor-Rex Code 1918) on a Carver Press.This test was strictly comparative.

Prior to the experiment, the die walls and punch faces of the CarverPress, which was utilized to measure the pressure-hardness profiles,were swabbed with 5% solution of stearic acid in chloroform and allowedto dry. One-half gram of the test material was placed in the die andcompressed on the Carver Press at various pressures, maintaining aconstant dwell time of 10 seconds in all cases. The compressed tabletwas ejected from the die by pushing out with the upper punch and itshardness (breaking strength) was determined on the Strong Cobb Hardnesstester. Five tablets were compressed at each pressure level, and theiraverage hardness value determined. Table 1 indicates thepressurehardness values of dextrose monohydrate. dehydrated dextrose,anhydrous dextrose and Royal-T.

TABLE 1 Pressure-Hardness Comparison Expressed in S.C.H.U.

HARDNESS VALUE IN S.C.H.U. AT:

"N.T. Not Tested "'35. Beyond Scale Accelerated Stability Study Thistest is conducted by taking tablets from each batch and packing the samein a wide-mouthed bottle which is tightly stoppered and storing the samein a tray-type dryer at 50C for 7 days. The tablets are then removed andsubjected to tests for hardness, disintegration, and friability. Anychange in physical appearance is thereafter noted.

The following examples further illustrate the present invention and willenable others skilled in the art to understand it more completely. Itshould be understood, however, that the invention is not limited solelyto the particular examples given below. The parts are parts by weight,unless otherwise indicated.

EXAMPLE 1 Evaluation of Pressure-Hardness Profile on DextroseMonohydrate, Dehydrated Dextrose, Anhydrous Dextrose, And Royal-TObtained on Carver Press The above data are indicative that all of thedextrose exhibit poor compressibility and. therefore, they are notsuitable as direct compression vehicles. The Royal- T product withoutany active ingredient exhibited a satisfactory compressibility profile.

EXAMPLE 2 Evaluation of Mixtures of Various Ratios of DextroseMonohydrate and Maltodextrin Prepared by Different Methods, on CarverPress a. Dry Blends of Dextrose Monohydrate and Maltodextrin:

Four 1 killogram batches of a dry blend of dextrose monohydrate and amaltodextrin (Mor-Rex Code 1918) were prepared in ratios of 95/5, 80/20,/35 and 50/50, respectively, in 21 Hobart Bowl Mixer. Each of the blendswas mixed for 7 minutes, and subjected to a pressure-hardness profileevaluation on a Carver r s tThsxssa tsera e forth in T b ""85. BeyondScale Based upon the data in Table 2, it is quite evident that dryblends of a crystalline sugar such as dextrose and a maltodextrin wouldnot be suitable as a vehicle for carrying high levels of apharmaceutically active in- This experiment illustrates the granulationof various levels of a mixture ofdextrose monohydrate and maltodextrinwith various solutions containing inaltodextrin dissolved therein.

g sgzf smlcc hurdnessnlullucs t: g mlxtum about 3 A calculated quantityof dextrose monohytlrate was 7OL111LS are enera ess an l k screenedthrough a No. 20 sieve (to remove any lumps! b. Dextrose MonohydrateGranulated with Aqueous and mixed with varying amounts otmaltodextrin(Mon Solutions Containing a Maltodextrin: Rex Code 1918) in a HobartBowl Mixer for -7 min Five 1 killogram batches of dextrose monohydrate10 utes- Welght i m eilch Mich l were each granulated with 30 ml. ot'asolution containlogmmeach mlxwre there was added 50 of 5, 10 Q0 30 d 40%W/\ Qffl l l r i (M solution containing dissolved therein themaltodextrin Rex Code 1918, a waxy starch hydrolysate having a (Mor-RexCode 1918) to obtain a damp mass. The DE. of about 9l3 which readilydissolves in water in damp mass was mixed an additional 7 minutesfollow- ConCentrations of up 0 0 he granulation ing the addition of themaltodextrin solution to cause P y ildflllllg the multodexmngranulation, whereupon the granulated damp mass was solution to thedextrose to obtain a damp mass. The Wm SCI-gelled through 3 6 Sic. anddried in an m ll f l i thoroughly mlxcd l g N fi oven to a finalmoisture content of 8.2 to 8.0%. The M u m f W 1 0 dried, granulatedproducts were evaluated on a arvcr sieve and dried in an oven to a finalmoisture content I Press to ascertain their ability to foinicommercially acot 5.2 to 5.8 /r. lhe moisture content was determined 4ceptable tablets. lhe details of the preparation and the on an ()hausMoisture Determination Balance. The H hcmilm Clcmum was Set at a pointcurrcsponding to results of the hardness profile evaluation me set loith100C. and the timer was set for 60 minutes. The loss m Table in weightwas noted every 15 minutes until there was no further loss. Thepercentage moisture lost was read [ABLE 4 otl the scale directly. Allthe granulations were dry screened to obtain a particle size such that100% passed through a No. 16 screen and 4992 passed through a No. 80screen. tThejscieening" described Quantity g herein and throughout thisspecification was conducted Quantity ()t (iranulate HARDNESS \'.\i.iiison a Syntron Test Sieve Shaker. Model: TSSZSB. man 01 Maltot\ ilb 510kufacturcd by the Syntron Company. Homer City. Pa, Dextrose d xtrin Msoil. of zltliiio 4|(li00 0:100 and U.S. Standard Sieves (A.S.T.M.specifications). (11mm) lgrmm maiuifactured by Fisher ScientificCompany. New 900 30% N York. New York.) All the granulations were subected s50 150 20 14.3 Isa its. to the pressure-hardness profileevaluation on the Car- H i /1 .i \ci l css. The details of the amountsof the solvents 8W 200 30% um :12 B5. used in each batch and the resultsof the pressurehardness profile are set forth in Table 3. 40 as. iittmascat TABLE 3 Quantity Quantity ()l Of HARDNESS VALUE lN S.C.H.U. AT:Dextrose (W/V Aq. Solvent 2000 4000 6000 8000 10.000

(grams) Sol. No. IHtt) Used lhs. lbs. lbs. lbs. lbs.

i) 10 30 ml. 5.0 12.2 16.6 17.0 17.2

1000 20% 30 ml. 5.0 14.6 l8.4 22.8 25.0

I000 30% 30 mi. 5.0 14.x 23.6 28.0 23.2

I000 40) 30 ml. 0.0 14.4 22.8 26.4 9.6

EXAMPLE 3 Granulation of Dextrose Monohydrate-Maltodextrin Mixture withAqueous Solutions Containing Maltodextrin The above data are indicativethat the granulation of a mixture of a crystalline sugar such asdextrose and at least about 10% by weight of a maltodextrin with anaqueous solution containing dissolved therein a maltodextrin provides atabletting composition having excellent hardness profiles atcommercially utilized pressures. Based upon the above hardness profilevalues of the foregoing granulations. these compositions can be used asdirect compression tabletting compositions. whereas the compositionsdescribed in Examples 1 and 2 (with the exception of Royal-T. which haslimited capacity to carry high levels ofpharmaeeutical materials) arenot acceptable as direct compression vehicles.

EXAMPLE 4 Evaluation ot'Compressibility and Carrying Capacity ofDextrose-Maltodextrin Granulated Direct Compression Vehicles 16 per tothe dies under operating conditions was observed and noted.

Each of the active ingredients (ascrobic acid (granular), as supplied byHoffman-LaRoche Inc. and ace1- aminophen (APAP), special power. suppliedby S. B.

Penick & Co.) were mixed with the granulated direct In this experiment,the compressibility and carrying compressionvehicle in a proportion of50 50% in a capacity ofthe dextrose-maltodextrin granulated directHobart Bowl Mixer for 57 minutes. Then. 0.5% to compression vehicle wasevaluated. The granulated ve- 0.75% by weight of magnesium stearate wasmixed with hicle used herein was prepared in the same manner dethevehicle and active ingredient as a lubricant. The scribed in Example 3by admixing 80% by weight of mixture was then fed into the tablet press.described dextrose monohydrate with 20% by weight of the malabove inthis Example. In the event that tablets were todextrin (Mot-Rex GradeI918, a waxy starch hydronot formed with a given mixture of activeingredients ly having it DB of and thereafter g fln and granulateddirect compression vehicle, the ratio ing the admix ure ith a 2 quSOIUIiOn 0f 15 was altered to increase the amount of vehicle while themaltodextrin (50 ml. ofsolution per 1,000 grams of lowering the level ofthe active ingredient. This procedextrose monohydrate and maltodextrinadmixture). dure was followed until the ratio which produced ac- Theparticle size otthe direct compression vehicles uticeptabletablets underidentical operating conditions lized in this experiment was such thatthey passed was produced. through a No. sieve. 20 Acceptable tablets aredefined as those which pos- The vehicles with and without the activeingredient sess minimum friability, effective hardness and rapid wereformed into tablets in a Stokes Model 8-2, 16 stadisintegration time.Samples of tablets produced at diftion rotary tablet machine which hadbeen set up with ferent pressures were taken and subjected to tests forfour inch s.c. tooling and a standard feed frame to hardness, weightvariation, friability. disintegration and enable gravity feed. Allsamples of the granulation were 5 stability. The details of theseexperiments and their refirst inspected for physical appearance. In eachinsults are tabulated in Table 5.

TABLE 5 EVALUATION Tablet Formulation 71 Disinte- "/1 Active LubricantTahlet gration Ascorbic Magnesium Hardness In Time Friahility Acld'APAPI Stearate S.C.H.U. In Min /1 0.5 a. 24.l a. 7.5 a. 0.l2 b. 17.3 b.7.5 b. 0.22 c. 8.8 c. 7.0 e. 0.21 0.5 t 7.5 10.5 0.46 25 0.75 10.0 10.50.00

ave

stance, 0.5% concentration of magnesium stearate was used as a tabletlubricant. The tablets were prepared at the maximum load obtainable,which was determined by gradually increasing the press pressure until adistinct knocking sound caused by a pressure overload was heard. andthen easing off on the pressure until the knocking sound ceased. Thehardness values for tablets produced at maximum pressure were obtainedand recorded. The operating press pressure was then reduced to producetablets with hardness values approximately one-third of the maximum andtwo-thirds of the maximum readings. In this manner, tablets wereobtained with three different hardness values, ranging from onethird tomaximum hardness for each material evaluated. The tablets were evaluatedfor weight variation, hardness, friability, disintegration andstability. The die till in all cases was adjusted so as to producetablets weighing 0.5 gram. The flow of the base from the hopges of thesereadings were reported as Mean Hardnessin Strong Cobb Hardness L' nits.The hardness lL'SItilVItS actuated by hand at 5 strokes per minute.

In each instance, the granulated direct compression composition wasindicated as having excellent cornpressibility characteristics andcarrying capacity. The granulated direct compression compositionexhibited excellent flowtl'rom the hopper to the dies of the tabletpress. However. the flow properties of the APAP compositions were notquite as good as the ascorbic acid containing compositions. The weightvariation of the TABLE 6 FORMULATION ACCELERATED STABILITY STUDY /1Active 70 Lubricant Hardness Disintegration Physical Ascorbic MagnesiumS.C.H.U. Time In Min. 7: Friability Appearance" Acid APAP StearateBefore After Before After Before After Before After 0.5 24.1 8.5. 7% 8%0.12 0.10 White A 17.3 8.5. 7% 7% 0.22 0.06 White A 8.8 B.S. '7.0 7%0.21 0 White A 30 0.5 7.5 8.5. 10% 11.0 0.46 0.08 White A 25 0.75 10.020.4 16.0 16.0 0.9 006 White A "Stored at 50"C for 7 days. 'Ascorbicacid granular. APAP (special powder, 5. B. Penick 8:. Co.).

w s. m.-. h

The results tabulated in Table 6 clearly reveal that the granulateddirect compression vehicles of the invention provide excellent tablets.The Accelerated Stability Studies indicate that there is a substantialincrease in tablet hardness with a noticeable decrease in friability andno change in the disintegration time of the tablets. All of the tabletshad an excellent white appearance.

EXAMPLE 5 In this experiment, the ilowability, compressibility, andcarrying capacity of granulations of different particle sizes arecompared.

In each of the tests, the vehicle was prepared by the granulationprocess of Example 3, wherein 80% by weight of dextrose monohydrate wasadmixed with 2071.11 weight of the maltodextrin (Mor-Rex Code 1918. awaxy starch hydrolysate having a DB. 019-1 3) bonate, aluminum hydroxidegel, dried; magnesium trisilicate, dried; (all three supplied by RugarChemical Co, New York), acetaminophen (APAP) regular powder, (assupplied by S. B. Penick & Co.) as indicated in Table 7. Each of thesamples tested contained a lubricant. The mixtures of the vehicle andthe active ingredient were placed in a Colton Model No. 204. 4 StationRotary tablet machine which had been set up with /8 inch S.C. toolingand a standard feed frame to enable gravity feed. The die fill in allcases was adjusted so as to produce tablets weighing 0.5 gram. The flowof the base from the hopper to the dies under operating conditions wasobserved and noted. Also, each of the mix- TABLE 7 DETAILS OFEXPERIMENTS ON CAPACITIES OF DIFFERENT PARTICLE SIZE RANGES OFGRANULATED VEHICLE Granu- FORMULATION lation 70 ACTIVE LUBRICANTEVALUATION [particle sodium Aluminum size Magnesium Hydroxide MagnesiumHardness In Disintegration range) carbonate APAP Trisilicate Gel. DriedStearate Talc S.C.H.U. in Min. Friability +200 0.75 19.0 12.0 0.05 9.512.0 0.14 30 1.0 5.0 20 0.29 15 2.0 5.0 14 Caps 20 2.0 1.0 6.0 62 0.2 201.0 1.0 8.5 79 0.19

and thereafter the admixture was granulated with a 20% W/V aqueoussolution of the maltodextrin (50ml. of the solution per 1.000 grams ofdextrose monohydrate and maltodextrin admixture). Each of thegranulations tested was passed through a Fitz Mill using a suitablescreen (No. 2A or No. 1) with knives forward at medium speed. Thecomminuted granulations were then hand sieved so as to obtain threeparticle size ranges, viz.: 20 +60. 40 +100, and -100 +200. Thegranulations (except the controls which did not contain activeingredient) were dry blended with sodium bicar weight variation (U.S.P.)test was also good to excel 19 lent. However, the 20 +60 and 40 +100particle size ranges illustrated the best uniformity.

' EXAMPLE 7 This experiment compares the vehicles of the presentinvention alone or in combination with various actives TABLE 8 DETAILSOF EXPERIMENTS ON CAPACITY OF GRANULATED VEHICLE AT DIFFERENT MOISTURECONTENT LEVELS FORMULATION Granulated ACTIVE LUBRICANT EVALUATIONVehicle Sodium Magnesium Aluminum Hardness Disin- Moisture Tri-Hydroxide Magnesium Capping, In tegration Content carbonate APAPsilicate Gel, Dried Stearate Talc If Any S.C.H.U. In Min. Friability 4.20.75 10.2 9.0 0.06 (i 0.2%) 0.75 8.7 13.0 0.93 15 1.25 Slight 8.2 18.00.63 25 2.0 1.0 6.5 79 0.11 25 1.0 1.0 8.2 89 0.2

r 4 r at various moisture content levels. EXAMPLE 8 The vehicle used inthis experiment was prepared in I the same manner as previouslydescribed in Examples 3 6. The vehicle was a granulated admixture of 80%by weight of dextrose monohydrate and 20% by weight of the maltodextringranulated with a 20% W/V solution of a maltodextrin. The finalgranulated admixture was screened to a particle size range of +100. Thegranulation was dried in an oven at different temperatures and fordifferent lengths of time so as to obtain at least three differentmoisture content levels, 8.0, 4.0 and 2.0%. by weight. The tablets wereprepared on a Colton Model No. 204, 4 station rotary tablet machine inthe same manner described in the previous examples. The tablets wereevaluated for weight variation, hardness. friability and disintegration.All four active medicinal ingredients (described in Table 8) which hadbeen dry blended with the vehicle of the invention were selected toevaluate the capacities of the granulations in the same mannerpreviously described. The details of the experiment are set forth inTable 8.

As it can be seen from the data in Table 8, there was no significantdifference in the compressibility and carrying capacity of thegranulation at higher and lower moisture content levels. The tabletsmade from the granulations with lower moisture content were checked forcapping and capping of the tablets was not ob- This experiment wasperformed to evaluate the carrying capacities of the granulations of thepresent invention with additional active medicinal agents.

Each of the active ingredients (ascrobic acid (type S); calciumsalicylate; ferrous sulfate (exicated); and Vitamin E acetate; 50% SD.)were mixed with the granulated vehicle of Example 3 and tested inexactly the same way as described in Example 4. Each of the blendedmixtures of granulated vehicle and active medicinal ingredient hadexcellent flow characteristics from the hopper to the tablet die. Thetablets also had a very narrow weight variation. All of the activeingredients were carried very well and the resulting tablets were ofextremely high quality, having a friability of less than 2%. Sodiumsalicylate was carried the least and it required a larger amount (2%)oflubricant. Vitamin E acetate (111) was carried up to 55%. The additionof 0.25% Cab-O-Sil as a glidant was extremely helpful in aiding the flowcharacteristics of the blend from the hopper to the tablet die. Calciumlactate and ferrous sulfate, exicated, were carried up to 35% and hadexcellent hardness .and friability characteristics. Ascrobic acid (typeS) at the 20% level produced excellent tablets having less than 1%friability and a hardness value of about 6. The details of theexperiments and results are tabulated in Table 9.

TABLE 9 DETAILS OF EXPERIMENTS ON CARRYING CAPACITIES OF GRANULATEDVEHICLE WITH ACTIVE MEDICINAL INGREDIENTS FORMUATION Active ActiveCarried "/1 LUBRICANT EVALUATION Medicinal By Granulated MagnesiumHardness Disintegration "/1 Agent Vehicle Stearate Talc Cab-O-Sil InS.C.H.U. In Min. Friability Ascorbic 20 0.5 5.8 8.5 0.21 Acid Vitamin EAcetate 55 0.5 0.25 4.0 16.0 0.04

DETAILS OF EXPERIMENTS ON CARRYING CAPACITIES OF GRANULATED VEHICLE WITHACTIVE MEDICINAL INGREDIENTS Ascorbic Acid (type S), Hoffmunla Roche.New Jersey. Vitamin F. Acctatc (50% SD). Hoffman-La Roche. New Jersey.

EXAMPLE 9 This experiment was performed to determine the effect ofSta-Rx 1500 (available from A. E. Staley Mfg. Co., Decatur, III.) on thedisintegration time ofthe tablets of the granulations per se, as well asin combination with various active medicinal agents.

The same granulated vehicle used in the previous Example 3 was employed.which was an admixture of 80% by weight dextrose monohydrate and of thewater soluble maltodextrin granulated with a 20% W/V solu- FORMUATIONActive Active Carried 7r LUBRICANT EVALUATION Medicinal By GranulatedMagnesium Hardness Disintegration 7r Agent Vehicle Stearate TalcCab-O-Sil In S.C.H.U. In Min. Friability Calcium '35 1.0 12.5 12.0 0.14I Lactate 1 Ferrous Sulfate. 0.5 7.6 25 0.31 Exicated Sodium 10 2.0 5.023 1.4 Salicylate ments measured less than 1%. All of the tablets hadgood hardness values. The hardness value for Vitamin E acetate tabletsranged from 3.8 to 4.0, simply because of the reference pressure for thecontrol tablets to produce a hardness value of 10.8. The hardness valueof these tablets could be increased to about 6 or TABLE 10 EFFECT OFSTA-RX 1500 AS A DISINTEGRANT ON GRANULATED VEHICLE WITH AND WITHOUTACTIVE MEDICINAL INGREDIENTS FORMULATION 7c ACTIVE Vitamin E 7cLUBRICANT EVALUATION Acetate Calcium Magnesium Capping, HardnessDisintegration 7t (509? SD.) Lactate Stearate Talc Cab-O-Sil Sta-Rx 1500If Any In S.C.H.U. In Min. Friability 0.75 10.8 8.5 0.07 0.75 10% Slight11.9 5.0 0.24 55 0.5 0.25 4.0 16.0 0.04 55 0.5 025 10% 3.8 12.0 0.08 1.012.5 12.0 0.14 35 1.0 10% Slight 12.4 8.0 021 tion of the maltodextrin.The dried granulated vehicle EXAMPLE 1() was screened to obtain a meshsize in the range of +100. The screened granulated vehicle (except thecontrol) was blended with Sta-Rx 1500 to obtain 10% by weight of Sta-Rxof the total mixture. The Sta-Rx 1500 was also added to the formulationscontaining the active medicinal ingredients, displacing the granulateddirect compression vehicle. The tablets were prepared in the same manneras described in Example 4, keeping the hardness the same as the tabletswithout Sta-Rx The tablets were evaluated for their weight variation,hardness, friability and disintegration. The addition of the directlycompressible starch, Sta-Rx 1500, did not effect the carrying capacityof the granulated vehicle of the invention. However. very slight cappingwas observed in the case of the calcium lactate formulation] This resultwas expected. since tablets containing starches have a tendency to cap.There was a decrease in disintegration time for the tablets containingSta-Rx 1500, as compared to those tablets without it. The reduction oftime was about one-third of the original time. The flow from the hopperto the tablet die for all samples was excellent. The friability in allofthe experi- This experiment was conducted to evaluate the rate ofmoisture pick-up by the granulations of the present invention per se,and in combination with active medicinal agents at a given relativehumidity to ascertain the stability of the active medicinal agents withthe granulated vehicle and the performance of the formulationscontaining the granulated vehicle under industrial working conditions,where a whole batch runs for eight hours or more, when moisture pick-upis possible.

The experiment was performed using the same granulated vehicle used inthe previous Examples which had been prepared by admixing by weight ofdextrose monohydrate with 20% by weight of the maltodextrin. andthereafter granulating the admixture with a 20% W/V aqueous solution ofthe maltodextrin (50 ml. of solution per 1,000 grams of dextrosemonohydrate and maltodextrin admixture). Vitamin C and Vitamin E acetatewere blended with several samples to provide 20 and 55% by weight of theactive medicinal agent in the total blend, respectively. The rate ofmoisture pick-up of the granulated vehicle. per se. and in ct'imbinationwith the active medicinal agents was studied at 50%, 70 and 90% relativehumidity at room temperature.

The moisture pick-up of the samples tested was determined using thebelow-described procedure.

The Rosano Surface Tensiometer, Model: LG, manufactured by the FederalPacific Electric Company, N.J., was employed in conjunction withScheibler Desiccators, containing constant relative humidity solutions.

One gram of the test material which was placed in an aluminum pan(supported by a wire ring) was hooked onto the Surface Tensiometer witha thread passing through a 2-inch length of rubber tubing partly slippedover a 3-inch length of plastic tubing. The glass tubing was fitted intothe tubulature of the desiccator top through a one-hole rubber stopper.The test material, the aluminum pan with the ring, the nylon thread werecounterbalanced by necessary weights to produce a tensiometer reading of0.00 mg. Readings were taken at the end of each hour and the increase inweight was noted.

All of the samples exhibited very little moisture pickup. The samplessubjected to 50% relative humidity ex hibited a maximum moisture pick-upafter 4-5 hours of less than 2.8%, by weight (increase in weightattributed to moisture pick-up). The samples subjected to 70% relativehumidity exhibited a maximum moisture pickup after about 5 hours of lessthan 6%, by weight. The samples subjected to 90% relative humidityexhibited a maximum moisture pick-up after ll hours of less than byweight. Based upon the results of the above moisture pickup tests, it isapparent that the granulated vehicles, per se, or in combination withthe active medicinal agents are not troubled by moisture pick-up whenexposed to relative humidities of less than about 75%. This desiredresult is quite unexpected in light of the propensity of dextrosecontaining compounds to be hygroscopic, i.e., they tend to pick-upmoisture upon standing.

EXAMPLE ll This experiment demonstrates the excellent density and fluffcharacteristics possessed by the granulated vehicles of the presentinvention, which characteristics enable the vehicle to have the goodflow properties from the hopper to the tablet die. As it is well-known,the tablet thickness actually depends on the volume occupied by thevehicle in the die cavity. Tablet thickness is related to the density ofthe granulation as volume and is inversely proportional to the density.Thus, the denser the granulation, the less volume will be occupied at agiven weight, producing thinner tablets. The thickness of the tabletsdetermines the choice of a given packaging unit and even the toolings tobe used in their manufacturing. This Example determines the fluff andtop densities of the granulations; first, the weight of the material ata given volume, and secondly, the volume is evaluated at a given weightof material. In each test, the granulated vehicle was prepared aspreviously described in Example 3, using 80% by weight of dextrosemonohydrate and 20% by weight of the maltodextrin.

The details of the procedure employed to determine the fluff density andtop density of the granulated vehicle of the invention are as follows:

Fluff Density Each granulated vehicle sample was poured down a gentleslope into a tarred l0-ml. cylinder. The weight was reported as FluffDensity in grams/ml.

Top Density Each granulated vehicle sample (50 grams) was accuratelyweighed and transferred to a .l00-ml. cylinder. The cylinder was gentlytopped on a thick layer of cloth, until no further perceptible decreasein volume was observed. The weight of the granulations was divided bythe volume obtained, and the result was reported as Top Density" ingrams/ml.

The results of the tests revealed that the granulated vehicle tested hada Fluff Density of 0.65 gram/ml. and a Top Density of 0.71 gram/ml.These values are indicative of excellent characteristics of thegranulated vehicles of the present invention.

EXAMPLE 12 Several granulated vehicles were prepared utilizing theunique procedure described in Example 3, except that in place of Mor-RexCode 1918, an acid hydrolysate having a DB of about 15 (Frodex,available from American Maize-Products), an enzyme hydrolysate having aE.E. of about 5 (Mor-Rex P908), and two dextrins (Globe Dextrin andExcello Dextrin, available from CPC International Inc.) were employed inamounts of l0, 20 and 30% by weight in the initial blend with thedextrose monohydrate. The respective maltodextrin or dextrin was placedin water and the solution or dispersion (containing 20% W/V of themaltodextrin or dextrin) was used to granulate the blend. The blendswere dried to a moisture content of 3-5% and screened of oversizegranules above a No. 14 mesh. Each of the granulated vehicles was mixedwith 1.0% magnesium stearate for lubrication and was formed into tabletson a Model F single stroke tabletting machine set at a ratio of 45strokes per minute and at 1% tons of pressure.

In all instances, the granulated vehicles were freeflowing and hadacceptable compressibilities. Slight scoring of tablets was observed inthe vehicles prepared from the acid hydrolysate (Frodex) and Mor-RexP908, therefore, necessitating a higher amount of lubricant or inclusionof an anti-adherent. From a hardness and friability standpoint, allblends made acceptable tablets. All of the granulated vehiclesdemonstrated very little hygroscopicity at 50, and 90% relativehumidity. The acid hydrolysate (Frodex) containing vehicles. However,the acid hydrolysate containing vehicles were slightly more hygroscopicthan the other vehicles tested. The dextrin containing vehicles, whilethey provided suitable tablets, were not acceptable because the tabletspossessed a yellow color and had a burnt flavor. Thus, it is necessaryto employ the maltodextrins to product commercially acceptablegranulatedvehicles for use in the pharmaceutical industry.

As it can be seen from the foregoing evidence, the present invention hasnow provided a unique granulated vehicle having an unusual structuralintegrity and density. The structural integrity and density of thegranulated vehicles provides a tabletting composition having excellentflowability and capability of forming strong, hard and substantiallynon-friable tablets, even when the tablet contains up to about by weightof the tablet, a pharmaceutically active material. By referring to asubstantially non-friable tablet, it is meant a tablet which loses lessthan about 1% by weight, as determined by the Roche test describedhereinabove.

While the invention has been described in connection with specificembodiments thereof, it will be understood that it is capable of furthermodification, and this application is intended to cover any variations,uses, or adaptations of the invention following, in general, theprinciples of the invention and including such departures from thepresent disclosure as come within known or customary practice in the artto which the invention pertains and as may be applied to the essentialfeatures hereinbefore set forth, and as fall within the scope of theinvention.

1 claim:

1. A method for producing a direct compression ve hicle for tablettingcomprising:

a. admixing a crystalline sugar with from about 10 to about 50% byweight, based upon the weight of said vehicle, ofa maltodextrin having ameasurable dextrose equivalent value not substantially above about 20 toform a uniform admixture,

b. concurrently agitating and spraying said admixture with an aqueoussolution containing dissolved therein a maltodextrin having a measurabledextrose equivalent value not substantially above about 20, said aqueoussolution of dissolved maltodextrin being present in an amount sufficientto provide a damp mass of said uniform admixture and to causegranulation of said uniform admixture, and

c. drying said granulated uniform admixture to a moisture content oflessthan about l% by weight, based upon the weight of said vehicle.

2. The process of claim 1, wherein said crystalline sugar is dextrose.

3. The process of claim 2, wherein the dextrose is a centrifuge cakecontaining up to about l6% by weight moisture, based upon the weight ofthe centrifuge cake.

4. The process of claim 1, wherein said crystalline sugar is admixedwith from about 15 to about 35% by weight of said maltodextrin, basedupon the weight of said vehicle.

5. The process of claim 1, wherein said aqueous solution contains fromabout to about 40% weight- /\'olume solution of said maltodextrin.

6. The process of claim 1, wherein said maltodextrin is a waxy starchhydrolysate having a dextrose equivalent value in the range of fromabout 9 to about 13 and a descriptive ratio of at least about 2, saiddescriptive ratio being the sum of the percentages (dry basis) ofsaccharides of the maltodextrin with a degree of polymerization of 1 to6 divided by the dextrose equivalent value.

7. A method for producing a direct compression vehicle for tablettingcomprising:

a. admixing a crystalline dextrose having a moisture content of up toabout 16% by weight with from about to about 35% by weight, based uponthe weight of said vehicle, of a maltodextrin having a measurabledextrose equivalent value not substantially above about 20 to form auniform admixture,

b. concurrently agitating and spraying said uniform admixture with anaqueous solution containing dissolved therein from about l()% to about40% weight/volume of a maltodextrin having a measur' able dextroseequivalent value not substantially above about 20. said aqueous solutionof dissolved maltodextrin being present in an amount sufficient toprovide a damp mass of said uniform admixture,

c. agitating said sprayed uniform admixture to uniformly interminglesaid crystalline dextrose and maltodextrin with said aqueous solution tocause granulation of said admixture, and

d. drying said granulated uniform admixture to a moisture content ofless than about 10% by weight.

8. The method of claim 7, wherein the crystalline dextrose is admixedwith from about 20 to about 30% by weight, based upon the weight of saidvehicle, of said maltodextrin.

9. A directly compressible tabletting vehicle comprising a granulatedmixture of a crystalline sugar and from about 10 to about 50% by weight,based upon the weight of said vehicle, of a water soluble maltodextrinhaving a measurable dextrose equivalent value not substantially aboveabout 20, said granulated mixture containing less than about 10% byweight moisture, based upon the weight of said vehicle, said directlycompressible tabletting vehicle in admixture with up to about by weight,based upon the weight of said vehicle, of at least one pharmaceuticallyactive ingredient, being characterized as capable of being formed bydirect compression at a pressure as low as about 2000 pounds into hard,substantially non-friable tablets having a Strong Cobb Hardness Unit(S.C.H.U.) value of at least about 6.

10. The directly compressible tabletting vehicle of claim 9, whereinsaid crystalline sugar is dextrose.

11. The directly compressible vehicle of claim 9, wherein said watersoluble maltodextrin is present in an amount ranging from about 15 toabout 35% by weight, based upon the weight of said vehicle.

12. The directly compressible vehicle of claim 9, wherein the moisturecontent of said vehicle is less than about 5% by weight, based upon theweight of said vehicle.

13. A method for preparing tablets comprising forming an admixture ofthe product of claim 9 and an active material, said product comprisingat least about 20% by weight of said vehicle, and compressing themixture into tablets.

14. A method for preparing tablets comprising forming an admixture ofthe product of claim 10 and an active material, said product comprisingat least 20% of said vehicle, and compressing the mixture into tablets.

15. The method of claim 14, wherein said active material is apharmaceutically active material.

16. The method of claim 15, wherein said pharmaceutically activematerial is a member selected from the group consisting of ascorbicacid, sodium salicylate, acetaminophen, sodium bicarbonate, aluminumhydroxide, magnesium trisilicate, Vitamin E acetate, calcium lactate,ferrous sulfate and mixtures thereof.

17. A directly compressed pharmaceutical composition in tablet form,comprising a dry-blended mixture comprising:

a. at least one pharmaceutically active ingredient present in an amountup to about 80% by weight, based upon the weight of said directlycompressed pharmaceutical composition; and Y b. a directly compressiblevehicle comprising a granulated mixture of a crystalline sugar and atleast about 10% by weight. based upon the weight of the directlycompressible vehicle, of a water soluble maltodextrin having ameasurable dextrose equivalent value not substantially above about 20,said directly compressible vehicle containing less than about by weightmoisture, said directly compressible vehicle being present in an amountof at least about 20% by weight, based upon the weight of said directlycompressed pharmaceutical composition, said directly compressedpharmaceutical composition being characterized as being hard andsubstantially non-friable, and being further characterized as having aStrong Cobb Hardness Unit (S.C.H.U.) value of at least about 6.

18. The directly compressed pharmaceutical composition of claim 17,wherein said crystalline sugar is dextrose.

19. The directly compressed pharmaceutical composition of claim 17,wherein said directly compressible vehicle comprises a granulatedmixture of dextrose monohydrate granulated with to about 35% by weight,based upon the weight of the vehicle, of a maltodextrin having ameasurable dextrose equivalent value not substantially above about 20.

20. The directly compressed pharmaceutical composition of claim 17,wherein said pharmaceutically active ingredient is a member selectedfrom the group consisting of ascorbic acid, sodium salicylate,acetaminophen, sodium bicarbonate, aluminum hydroxide, magnesiumtrisilicate, Vitamin E acetate, calcium lactate, ferrous sulfate andmixtures thereof.

21. The directly compressed pharmaceutical composition of claim 17,which additionally includes a small but effective amount of materialsselected from the group consisting of lubricants, coloring aids,disintegrants, binders and mixtures thereof.

22. A directly compressed pharmaceutical composition in tablet form,comprising a dry-blended mixture comprising:

a. ascorbic acid in an amount of up to about 80% by weight. based uponthe weight of said pharmaceutical composition; and

b. a directly compressible vehicle comprising a granulated mixture ofdextrose and about 15% to about 35% by weight, based upon the weight ofsaid vehicle, of water soluble maltodextrin having a measurable dextroseequivalent value not substantially above about 20, said vehiclecontaining less than about 10% by weight moisture.

said directly compressed pharmaceutical tablet being characterized asbeing hard and substantially nonfriable such that the tablet has aStrong Cobb Hardness Unit (S.C.H.U.) value of at least about 6.

23. The composition in accordance with claim 22, wherein saidcomposition contains ascorbic acid in an amount from about 15 to about35% by weight, based upon the weight of the tablet.

24. A directly compressible tabletting vehicle comprising a granulatedmixture of dextrose and from about l5 to about 35% by weight, based uponthe weight of the vehicle, of a water soluble maltodextrin having ameasurable dextrose equivalent value not substantially above about 20,said granulated mixture containing less than about 5% by weightmoisture, based upon the weight of said vehicle, said directlycompressible tabletting vehicle in admixture with at least onepharmaceutically active ingredient in an amount of from about l5 toabout 35% by weight, based upon the weight of the total composition,being characterized as capable of being formed by direct compression ata pressure as low as 2000 pounds into hard, substantially non-friabletablets having a Strong Cobb Hardness Unit (S.C.H.U.) value of at leastabout 6, said vehicle being further characterized as having a particlesize in the range of from about 40 to about mesh screen.

25. The directly compressible tabletting vehicle of claim 24, whereinsaid vehicle additionally contains a tabletting lubricant.

1. A METHOD FOR PRODUCING A DIRECT COMPRESSION VEHICLE FOR TABLETTINGCOMPRISING: A. ADMIXING A CRYSTALLINE SUGAR WITH FROM ABOUT 10 TO ABOUT50% BY WEIGHT, BASED UPON THE WEIGHT OF SAID VEHICLE OF A MALTODEXTRINHAVING A MEASURABLE DEXTROSE EQUIVALENT VALUE NOT SUBSTANTIALLY AOVEABOUT 20 TO FORM A UNIFORM ADMIXTURE, B. CONCURREENTLY AGITATING ANDSPRAYING SAID ADMIXTURE WITH AN AQUEOUS SOLUTION CONTAINING DISSOLVEDTHEREIN A MALTODEXTRIN HAVING A MEASURABLE DEXTROS EQUIVALENT VALUE NOTSUBSTANTIALLY ABOVE ABOUT 20, SAID AQUEOUS SOLUTION OF DISSOLVEDMALTODEXTRIN BEING PRESENT IN AN AMOUNT SUFFICIENT TO PROVIDE A DAMPMASS OF SAID UNIFORM ADMIXTURE AND TO CAUSE GRANULATION OF SAID UNIFORMADMIXTURE, AND C. DRYING SAID GRANULATION UNIFORM ADMIXTURE TO AMOISTURE CONTENT OF LESS THAN ABOUT 10% BY WEIGHT, BASED UPON THE WEIGHTOF SAID VEHICLE.
 2. The process of claim 1, wherein said crystallinesugar is dextrose.
 3. The process of claim 2, wherein the dextrose is acentrifuge cake containing up to about 16% by weight moisture, basedupon the weight of the centrifuge cake.
 4. The process of claim 1,wherein said crystalline sugar is admixed with from about 15 to about35% by weight of said maltodextrin, based upon the weight of saidvehicle.
 5. The process of claim 1, wherein said aqueous solutioncontains from about 5 to about 40% weight/volume solution of saidmaltodextrin.
 6. The process of claim 1, wherein said maltodextrin is awaxy starch hydrolysate having a dextrose equivalent value in the rangeof from about 9 to about 13 and a descriptive ratio of at least about 2,said descriptive ratio being the sum of the percentages (dry basis) ofsaccharides of the maltoDextrin with a degree of polymerization of 1 to6 divided by the dextrose equivalent value.
 7. A method for producing adirect compression vehicle for tabletting comprising: a. admixing acrystalline dextrose having a moisture content of up to about 16% byweight with from about 15 to about 35% by weight, based upon the weightof said vehicle, of a maltodextrin having a measurable dextroseequivalent value not substantially above about 20 to form a uniformadmixture, b. concurrently agitating and spraying said uniform admixturewith an aqueous solution containing dissolved therein from about 10% toabout 40% weight/volume of a maltodextrin having a measurable dextroseequivalent value not substantially above about 20, said aqueous solutionof dissolved maltodextrin being present in an amount sufficient toprovide a damp mass of said uniform admixture, c. agitating said sprayeduniform admixture to uniformly intermingle said crystalline dextrose andmaltodextrin with said aqueous solution to cause granulation of saidadmixture, and d. drying said granulated uniform admixture to a moisturecontent of less than about 10% by weight.
 8. The method of claim 7,wherein the crystalline dextrose is admixed with from about 20 to about30% by weight, based upon the weight of said vehicle, of saidmaltodextrin.
 9. A directly compressible tabletting vehicle comprising agranulated mixture of a crystalline sugar and from about 10 to about 50%by weight, based upon the weight of said vehicle, of a water solublemaltodextrin having a measurable dextrose equivalent value notsubstantially above about 20, said granulated mixture containing lessthan about 10% by weight moisture, based upon the weight of saidvehicle, said directly compressible tabletting vehicle in admixture withup to about 80% by weight, based upon the weight of said vehicle, of atleast one pharmaceutically active ingredient, being characterized ascapable of being formed by direct compression at a pressure as low asabout 2000 pounds into hard, substantially non-friable tablets having aStrong Cobb Hardness Unit (S.C.H.U.) value of at least about
 6. 10. Thedirectly compressible tabletting vehicle of claim 9, wherein saidcrystalline sugar is dextrose.
 11. The directly compressible vehicle ofclaim 9, wherein said water soluble maltodextrin is present in an amountranging from about 15 to about 35% by weight, based upon the weight ofsaid vehicle.
 12. The directly compressible vehicle of claim 9, whereinthe moisture content of said vehicle is less than about 5% by weight,based upon the weight of said vehicle.
 13. A method for preparingtablets comprising forming an admixture of the product of claim 9 and anactive material, said product comprising at least about 20% by weight ofsaid vehicle, and compressing the mixture into tablets.
 14. A method forpreparing tablets comprising forming an admixture of the product ofclaim 10 and an active material, said product comprising at least 20% ofsaid vehicle, and compressing the mixture into tablets.
 15. The methodof claim 14, wherein said active material is a pharmaceutically activematerial.
 16. The method of claim 15, wherein said pharmaceuticallyactive material is a member selected from the group consisting ofascorbic acid, sodium salicylate, acetaminophen, sodium bicarbonate,aluminum hydroxide, magnesium trisilicate, Vitamin E acetate, calciumlactate, ferrous sulfate and mixtures thereof.
 17. A directly compressedpharmaceutical composition in tablet form, comprising a dry-blendedmixture comprising: a. at least one pharmaceutically active ingredientpresent in an amount up to about 80% by weight, based upon the weight ofsaid directly compressed pharmaceutical composition; and b. a directlycompressible vehicle comprising a gRanulated mixture of a crystallinesugar and at least about 10% by weight, based upon the weight of thedirectly compressible vehicle, of a water soluble maltodextrin having ameasurable dextrose equivalent value not substantially above about 20,said directly compressible vehicle containing less than about 10% byweight moisture, said directly compressible vehicle being present in anamount of at least about 20% by weight, based upon the weight of saiddirectly compressed pharmaceutical composition, said directly compressedpharmaceutical composition being characterized as being hard andsubstantially non-friable, and being further characterized as having aStrong Cobb Hardness Unit (S.C.H.U.) value of at least about
 6. 18. Thedirectly compressed pharmaceutical composition of claim 17, wherein saidcrystalline sugar is dextrose.
 19. The directly compressedpharmaceutical composition of claim 17, wherein said directlycompressible vehicle comprises a granulated mixture of dextrosemonohydrate granulated with 15 to about 35% by weight, based upon theweight of the vehicle, of a maltodextrin having a measurable dextroseequivalent value not substantially above about
 20. 20. The directlycompressed pharmaceutical composition of claim 17, wherein saidpharmaceutically active ingredient is a member selected from the groupconsisting of ascorbic acid, sodium salicylate, acetaminophen, sodiumbicarbonate, aluminum hydroxide, magnesium trisilicate, Vitamin Eacetate, calcium lactate, ferrous sulfate and mixtures thereof.
 21. Thedirectly compressed pharmaceutical composition of claim 17, whichadditionally includes a small but effective amount of materials selectedfrom the group consisting of lubricants, coloring aids, disintegrants,binders and mixtures thereof.
 22. A directly compressed pharmaceuticalcomposition in tablet form, comprising a dry-blended mixture comprising:a. ascorbic acid in an amount of up to about 80% by weight, based uponthe weight of said pharmaceutical composition; and b. a directlycompressible vehicle comprising a granulated mixture of dextrose andabout 15% to about 35% by weight, based upon the weight of said vehicle,of water soluble maltodextrin having a measurable dextrose equivalentvalue not substantially above about 20, said vehicle containing lessthan about 10% by weight moisture. said directly compressedpharmaceutical tablet being characterized as being hard andsubstantially non-friable such that the tablet has a Strong CobbHardness Unit (S.C.H.U.) value of at least about
 6. 23. The compositionin accordance with claim 22, wherein said composition contains ascorbicacid in an amount from about 15 to about 35% by weight, based upon theweight of the tablet.
 24. A directly compressible tabletting vehiclecomprising a granulated mixture of dextrose and from about 15 to about35% by weight, based upon the weight of the vehicle, of a water solublemaltodextrin having a measurable dextrose equivalent value notsubstantially above about 20, said granulated mixture containing lessthan about 5% by weight moisture, based upon the weight of said vehicle,said directly compressible tabletting vehicle in admixture with at leastone pharmaceutically active ingredient in an amount of from about 15 toabout 35% by weight, based upon the weight of the total composition,being characterized as capable of being formed by direct compression ata pressure as low as 2000 pounds into hard, substantially non-friabletablets having a Strong Cobb Hardness Unit (S.C.H.U.) value of at leastabout 6, said vehicle being further characterized as having a particlesize in the range of from about -40 to about +100 mesh screen.
 25. Thedirectly compressible tabletting vehicle of claim 24, wherein saidvehicle additionally contains a tabLetting lubricant.